The prostate gland is known to become hyperproliferative and display a propensity toward carcinoma, with progression in age. As a result, the frequencies of benign prostatic hyperplasia (BPH) and prostate cancer increase dramatically in elderly men. The Insulin-like growth factor (IGF) system is being increasingly recognized as an important regulator of prostatic functions. Insulin like growth factor binding protein-2 (IGFBP-2) may play a significant role in prostatic growth because: (a) it is a major prostatic binding protein; (b) serum IGFBP-2 levels increase with age; and (c) circulatory levels of the protein are dramatically higher in prostate cancer patients compared to those with BPH, or in normal subjects. The role of IGFBP-2 in prostatic growth has not been studied to date. Our preliminary studies with prostate cancer cell lines suggest that IGFBP-2 potentiates the growth of prostate cancer cells by up-regulating IGF-I, while IGFBP-2 antibody (Ab) inhibits these effects. No significant growth modulating effects of IGFBP-2 or its antibody were found on normal prostate epithelial cells obtained from a 40 year old single donor. Based on the results of our preliminary studies, and the fact that prostate cancer develops in old age, I hypothesize that IGFBP-2 is involved in the age-dependent transformation of the prostate from normal to metastatic disease. I speculate that elevation of circulatory IGFBP-2 with age induces malignant transformations in the prostate by up- regulating IGF-I, and by modulating IGF cellular actions. To test my hypothesis, the specific aims of the current proposal are to: (1) study age-related and lobe-specific changes in the morphology and expression of IGF system components in the prostate of rodent models of spontaneous hyperplasia and prostatic carcinoma, and relate these to circulatory levels of IGFBP-2; (2) explore if exogenously administered IGFBP-2 or its antibody can modulate the incidence of malignant transformations in the prostate of rodent models of spontaneous hyperplasia and prostatic carcinoma; (3) examine if IGFBP-2 can modulate the tumorigenic potential of normal and malignant prostatic epithelial cells in vivo and in vitro, and (4) investigate the molecular mechanisms by which IGFBP-2 modulates the growth of normal and malignant prostatic epithelial cells. The importance of the proposed studies lies in the fact that besides establishing a knowledge base on age-related changes in the role of IGFBP-2 in the prostate, it will create new grounds for targeting IGFBP-2 in the early diagnosis, progression, management and treatment of prostate cancer, which affects a large population of elderly men.